Globoid Leukodystrophy (Krabbe's Disease) is a sphingolipidosis caused by an inherited deficiency of cerebroside beta-Galactosidase and other enzyme activities; the disease results in neuropathy and degeneration of white matter in the central nervous system. Canine globoid leukodystrophy (GLD) is an authentic animal model of human GLD. We plan to maintain a breeding colony of dogs to produce canine GLD offspring for current experimental and future therapeutic investigations. We shall quantify GLD lesion distribution in brain and spinal cord, select regions that are resistant vs. susceptible to GLD lesions, based on lesion incidence, and quantify regional morphologic and biochemical features to correlate these with regional resistance to GLD lesions. By experimentally producing Wallerian degeneration to challenge neurilemmal cells to autophagocytize myelin, we expect to assess the capacity of these cells to degrade myelin and ultimately to remyelinate axons. By producing experimental Wallerian degeneration in optic nerves we hope to assess the capability and fate of GLD oligodendrocytes, including investigation of the hypothesis that oligodendrocytes can autophagocytize myelin. We hope to describe GLD pathogenesis morphologically by examining early lesion formation in preclinical cases of GLD and by determining the sequence of pathologic events in GLD neuropathy. We shall investigate in vitro phagocytosis of sphingolipids by cell culture fibroblasts of normal, heterozygote, and GLD genotypes.